Transcript β-Lactam Antibiotics

Antibiotic Overview
Nathan P. Samsa, Pharm.D., R.Ph.
1
Objectives
• Briefly discuss pharmacokinetics
• Review basic pharmacology of the
various antibiotics
• Address indications and side effects
• Provide helpful mnemonics
• Correlate infectious diseases with
appropriate pharmacological therapy
2
“Basic” Pharmacokinetics
• “ADME”
–
–
–
–
Adsorption
Distribution
Metabolism
Excretion
• Pharmacokinetics:
– “How the body acts on the drug”
• Pharmacodynamics:
– “How the drug acts on the body”
3
How Can We Inhibit Bacteria?
• Bacteristatic
– Inhibits a vital pathway used in the growth
of the bacteria, but does not directly cause
death
• Bactericidal
– Disrupts bacterial function so much that
death will occur
4
What Manner Can We Kill?
• Time-dependent
– Drug concentration must remain constantly
above the minimum inhibitory concentration
(MIC)
• β-lactams, vancomycin
• Concentration-dependent
– Drug concentration must reach a certain
concentration, many times based on the area
under the curve (AUC)
• Fluoroquinolones
5
What Can We Disrupt?
•
•
•
•
•
Cell Wall
Folic Acid Synthesis
Nucleic Acid Synthesis
Ribosome
Cell Membrane
6
Cell Wall Inhibitors
7
Cell Wall Agents
• β-Lactams
–
–
–
–
Penicillins
Cephalosporins
Monbactams
Carbapenems
• Glycopeptides
8
β-Lactams
• Bacterial cell walls have 5-peptide chains
(L-ala—D-glu—L-lys—D-ala—D-ala) crosslinked by penicillin binding proteins (PBP)
• The β-lactam ring system looks like Dala—D-ala, where the PBPs will use the βlactam instead
• The β-lactam “pops open,” destroying the
PBP and halting further crosslinkingcell
wall weakenslysis
9
β-Lactam Subtypes
• All share a β-lactam ring, thereby having
the same mechansim of action (and
explaining the cross-sensitivity between
classes)
–
–
–
–
Penicillins
Cephalosporins
Monobactams
Carbapenems
10
Penicillin Classifications
• Narrow-spectrum penicillins
• Penicillinase-resistant penicillins
• Extended-spectrum penicillins
11
Narrow-Spectrum Penicillins
• Penicillin G (Pfzierpen®)-IM, IV, PO
– More active against Neiserra and anaerobes
• Penicillin V (Pen-Vee K®, Veetids®)-PO
– Keep it straight: V is not IV
• Good activity against Gram {+} cocci
• Anaerobic activity (except Bacteroides)
• Drug of choice for syphilis, gas
gangrene, and meningococcus
• No activity against aerobic Gram {-}
12
Penicillinase-Resistant Agents
• Cloxacillin (Cloxapen®)
• Dicloxacillin (Dynapen®)
• Methacillin (Staphcillin®)
– Discontinued in US
• Nafcillin (Nafcil®)
• Oxacillin (Prostaphlin®)
13
Penicillinase-Resistant PCNs
• Originally designed solely for coverage
against S. aureus (methicillin-susceptable
S. aureus [MSSA])
• Decreased activity against other bugs
• S. aureus becoming increasingly resistant
to this class (MRSA), as well as
Staphylococcus epidermidis
– Vancomycin treatment of choice for MRSA
• Eliminated hepatically
14
Extended-spectrum PCNs
• Aminopenicillins
• Carboxypenicillins
• Ureidopenicillins
15
Aminopenicillins
• Agents
– Ampicillin (Omnipen®, Principen®)
– Amoxicillin (Amoxil®, Trimox®)
– Bacampicillin (Spectrobid®)
• Broader spectrum over penicillin
–
–
–
–
Gram {-} aerobes
Listeria monocytogenes
Proteus mirabilis
E. coli
16
Carboxypenicillins
• Agents
– Carbenicillin (Geopen®)
– Ticarcillin (Ticar®)
• More coverage than the aminopenicillins
– Increased Gram {-} coverage
– Peudeomonas aeruginosa
• Ticarcillin 2-4× > Carbenicillin
– Enterobacter
• Carbenicillin concentrates rapidly in urine
17
Ureidopenicillins
• Agents
– Azlocillin (Azlin®)
• Discontinued in the US
– Mezlocillin (Mezlin®)
– Pipercillin (Pipracil®)
• Activity
– Maintains Gram {+} coverage
– Added Gram {-}
– Anti-pseudomonal activity
18
β-Lactamase Inhibitors
• Chemicals with no antibacterial activity
that irreversibly inactivate β-lactamase
– Sulbactam
• With ampicillin (Unasyn®)
– Tazobactam
• With pipercillin (Zosyn®)
– Clavulanate/Clavulanic acid
• With amoxicillin (Augmentin®)
• With ticarcillin (Timentin®)
19
Cephalosporins
•
•
•
•
•
•
Spectra of activity (generation)
Anaerobic activity (Cephamycins)
Anti-pseudomonal activity
Methyltetrazolethiomethyl side-chain
Metabolism/elimination
Cerebrospinal fluid penetrance
20
1st Generation Agents
• Cefazolin (Ancef®, Kefzol®)
• Cefadroxil (Duricef®)
– Cephalosporin analog of amoxicillin
• Cephalexin (Keflex®)
– Cephalosporin analog of ampicillin
• Cephalothin (Keflin®)
• Cephapirin (Cefadyl®)
• Cephradine (Anspor®, Velosef®)
21
1st Generation Cephalosporins
• Great Gram {+} activity
• No activity against enterococci
Listeria monocytogenes
or
• Mainstay of choice for uncomplicated
community acquired infections
• PEcK activity
– Proteus
– E. coli
– Klebsiella
22
2nd Generation Agents
•
•
•
•
•
•
•
•
Cefaclor (Ceclor®)
Cefamandole (Mandol®)
Cefmetazole (Zefazone®)
Cefoxitin (Mefoxin®)
Cefotetan (Cefotan®)
Cefonicid (Monocid®)
Cefprozil (Cefzil®)
Cefuroxime (Ceftin®, Zinacef®, Kefurox®)
23
2nd Generation Cephalosporins
• More Gram {-} activity than
generation agents
• Often used for UTIs and URIs
• HENPEcK activity
–
–
–
–
–
–
H. influenzae
Enterobacter* (rapid resistance occurs)
Neisseria
Proteus
E. coli
Klebsiella
1st
24
3rd Generation Agents
•
•
•
•
•
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•
•
•
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Cefdinir (Omnicef®)
Cefditoren (Spectracef®)
Cefixime (Suprax®)
Cefoperazone (Cefobid®)
Cefotaxime (Claforan®)
Cefpodoxime (Vantin®)
Ceftazidime (Fortaz®, Tazidime®)
Ceftibuten (Cedax®)
Ceftizoxime (Cefizox®)
Ceftriaxone (Rocephin®)
25
3rd Generation Cephalosporins
• Have even better Gram {-} coverage
than second generation agents
• Loses more Gram {+} coverage
• Extra coverage against Serratia and
Moraxella catarrhalis
26
4th Generation Cephalosporins
• Cefepime (Maxipime®)
– Has most of the Gram {-} coverage with
Gram {+} coverage
– Anti-pseudomonal activity
– No anaerobic activity
27
The Generation Progression
• As one moves up in cephalosporin
generation, more Gram {-} activity is
seen
• Consequently, Gram {+} activity is
decreased advancing in generation
• 4th generation has Gram {-} activity
without sacrificing Gram {+} activity
28
Keeping Generations Straight
• How can one keep them all straight?
• 1st generation:
– If the “f” sound is spelled “ph”, it HAS to
be a 1st generation (phirst)
• 3rd generation:
– If an “f” is followed immediately by a “d” or
“t”, it HAS to be a 3rd generation (third)
• 4th generation:
– “Cefepime is supreme!”
29
Cephamycins
• Cephamycins are a special subset of 2nd
generation cephalosporins with great
anaerobic activity
– Cefotetan
– Cefoxitin
• Mnemonic: Get a foxy tan on your back!
– Back is for bacteroides, a common anaeobic
bacteria
30
Anti-Pseudomonal Cephalosporins
• 3rd Generation
– Cefoperazone
– Ceftazidime
• 4th Generation
– Cefepime
• The 3rd generation anti-pseduomonal
agents lose even more Gram {+} activity
than other 3rd generation agents
31
MTT Side-Chain
• Methyltetrazolethiomethyl (MTT)
– Hypoprothrombinemia and
disturbing
synthesis
of
dependent clotting factors
bleeding
vitamin
by
K-
• Risk factors are renal or hepatic disease, poor
nutrition, the elderly, and cancer
– Disulfiram-like reaction
• Disulfiram is an agent that inhibits alcohol
dehydrogenase,
causing
an
increase
of
acetaldehyde, the agent that causes hangovers
32
MTT-Containing Cephalosporins
• Agents
–
–
–
–
Cefamandole
Cefmetazole
Cefoperazone
Cefotetan
• Mnemonic: I met a man with a perfect tan
33
Cephalosporin Elimination
• For the most part, all are renal with few
exceptions
• The “zones” are hepatic
– Cefoperazone
– Ceftriaxone
34
CSF penetrance
• 2nd Generation
– Cefuroxime
• Generally not used due to decreased efficacy
• 3rd Generation
– Cefotaxime
• Q6-8° dosing
• Agent of choice in neonatal meningitis (along
with ampicillin)
– Ceftriaxone
• Q12-24° dosing
• Agent of choice for adult meningitis
• Causes kernicterus in neonates
35
Monobactams
• Aztreonam (Azactam®)
• Resistant to most Gram {-} β-lactamases
• Activity
– Only Gram {-} coverage (spectrum
resembles aminoglycosides)
– Excellent activity against P. aeruginosa
– Superb Enterobacteriaceae activity
– No Gram {+} or anaerobic activity
36
Carbapenems
• More resistant to hydrolysis from βlactamases
• Very broad spectrum with coverage of
Gram {+} (not MRSA), Gram {-},
anaerobes, and Pseudomonas aeruginosa
• Higher incidence of seizure than other
β-lactam agents
37
Carbapenem Agents
• Agents
– Ertapenem (Invanz®)
– Imipenem (Primaxin®)
– Meropenem (Merrem®)
• Ertapenem
lacks
coverage
against
Pseudomonas
acinetobacter,
two
common nosocomial agents
38
Cilistatin
• Inhibits renal dehydropeptidase 1, an
enzyme which degrades imipenem in the
kidney brush border cells
• Given only with imipenem (Primaxin®)
• Has neither β-lactamase inhibitory
effects nor antibacterial activity
• Totally unrelated from the “statin”
cholesterol drugs (HMG-CoA Inhibitors)
39
Glycopeptides
• Vancomycin (Vancocin®)
• Teicoplanin (Targocid®)
40
Vancomycin
• Vancomycin makes five hydrogen bonds
to the D-Ala-D-Ala amino acids at the
end of the peptide cross-bridges
• It prevents them from being accessible
to the active site of the transpeptidases
(where the β-lactams work)
41
Vancomycin Spectrum
• Gram {+} aerobes
• MRSA
• Penicillin-resistant pneumococcus
42
Vancomycin SE
• Renal clearance
– Ototoxicity
– Nephrotoxicity
• These are points of contention as they are normally seen in
conjunction with aminoglycosides…is it the aminoglycoside,
or additive effect?
• Infusion related reactions:
– “Red Man Syndrome”
– Fever/chills
– Phlebitis
43
VRE
• Vancomycin Resistant Enterococcus
• Few options left:
– Quinopristin/Dalfopristin (Sinercid®)
• Coverage only against Enterococcus faecium,
none against Enterococcus faecalis
• Tip: Faecalis has a “hard c”, so it is harder to
treat
– Linezolid (Zyvox®)
• Covers both faecium and faeacalis
44
Folic Acid Synthesis
Inhibitors
45
Folic Acid Inhibitors
• “Sulfas”
– Inhibit dihydropteroate synthetase, an
enzyme involved in the synthesis of bacterial
folic acid
• Trimethoprim
– Inhibit dihydrofolate reductase, an enzyme
necessary for thymidine synthesis
• Both are bacteriostatic
46
Folic Acid Inhibitor Spectrum
•
•
•
•
Enterobacter
Chlamydia
Nocardia
Pneumocystis carnii
47
Folic Acid Inhibitor SE
• Rashes
– Stevens-Johnson syndrome
• Angioedema
• Hemolytic anemia
• Nephrotoxicity
– Via precipitation
metabolite
of
crystals
of
the
inactive
• Crosses the placenta
– Kernicturus
– Should be avoided in pregnancy and in children under
2 months of age
48
Nucleic Acid Synthesis
Inhibitors
49
Nucleic Acid Inhibitors
• Fluoroquinolones
50
Fluoroquinolones
• Inhibit DNA topoisomerase II (DNA
gyrase)
• Bacteriostatic
• Divided into generations; reverse of the
reverse
of
cepholosporins
(actual
classification varies between sources)
– Cephalosporins progress from Gram {+} to
Gram {-} activity, but loses Gram {+}
– Fluoroquinolones progress from Gram {-} to
Gram {+} activity, but retains Gram {-}
51
1st Generation FQs
• Nalidixic Acid (NegGram®)
• Gram {-} coverage only
–
–
–
–
Enterobacteraceae
E. Coli
Klebsiella
Proteus
52
2nd Generation FQs
• Agents
– Cinoxacin (Cinobac®)
– Enoxacin (Penetrex®)
• Pulled from market
– Lomefloxacin (Maxaquin®)
– Norfloxacin (Noroxin®)
• Increased Gram {-} spectrum
53
Advanced 2nd Generation FQs
• Agents
– Ciprofloxacin (Cipro®)
– Ofloxacin (Floxin®)
• Has increased Gram {-} coverage along
with atypicals
• Cipro has good Pseudomonas coverage
54
3rd Generation FQ Agents
• Agents
– Gatifloxacin (Tequin®)
– Grepafloxacin (Raxar®)
• Pulled from market
– Levofloxacin (Levaquin®)
• L-isomer
of Ofloxacin
– Sparfloxacin (Zagam®)
– Temafloxacin (Omniflox®)
• Pulled from market
• Same coverage as 2nd generation with moderate
Gram {+} activity
• Used in community acuquired pneumonia
55
4th Generation FQ Agents
• Agents
– Alatrofloxacin (Trovan® IV)
• Limited market availability d/t toxicity
– Gemifloxacin (Factive®)
– Moxifloxacin (Avelox®)
– Trovafloxacin (Trovan® PO)
• Limited market availability d/t toxicity
• Same as 3rd generation with anaerobic
coverage
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FQ Side Effects
•
•
•
•
•
•
•
Complexes with cations
Photosensitivity
CYP450 interactions
Renal elimination
QT prolongationTorsades de Pointes
Hepatic failure (Trovan®)
Tendon rupture
– Do not give if <18yo
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Ribosomal Inhibitors
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Anti-Ribosomal Agents
• Ribosomal Subunits
– 30s Subunit (Prokaryotic)≈40s (Eukaryotic)
• Tetracyclines
• Aminoglycosides
– 50s Subunit (Prokaryotic)≈60s (Eukaryotic)
• Macrolides
• Lincomycins
• Chloramphenicol
• Miscellaneous
– Streptogramins
– Oxazolidinones
59
Anti-Ribosomal Mnemonic
• Mnemonic:
– @30, Amina cycles
• (Aminoglycocide & Tetracycline)
– @50, Mac likes Nicole
• (Macrolide & Lincomycin & Chloramphenicol)
• Hey, they’re cheesy, but I’m desperate
for ideas!
60
30s Inhibitors
• Tetracyclines:
– Bind to amino acyl t-RNA portion of the
mRNA-ribosome complex
– Bacteriostatic
• Aminoglycosides
– Bind to the separated 30s subunit causing
misreading
– Bacteriocidal
61
Tetracyclines
•
•
•
•
Demeclocycline (Declomycin®)
Doxycycline (Vibramycin®)
Minocycline (Minocin®)
Tetracycline (Sumycin®)
62
Tetracycline Spectrum
• Gram {+} Bacilli
• Gram {-} Rods
• Gram {-} Bacilli
– H. influenzae, Vibrio cholera
• Spirochetes
– Borrelia burgdorferi (Lyme dz), treponema pallidum
(syphilis)
• Chlamydia
• Rickettsia rickettsii (Rocky Mt. Spotted Fever)
63
Tetracycline SE
• Chelates with cations
– Decreased absorption with dairy, calcium
– Deposition on calcified tissues
• GI upset
• Phototoxicity
• Demeclocycline
– Never used as an antibiotic because it can
induce nephrogenic diabetes insipidus
– Used in treatment of SIADH
64
Aminoglycocides
•
•
•
•
•
•
•
Amikacin (Amikin®)
Gentamicin (Garamycin®)
Netilmycin (Netromycin®)
Neomycin (Mycifradin®)
Kanamycin (Kantrex®)
Streptomycin
Tobramycin (Nebcin®)
65
Aminoglycocide Spectrum
• Gram {-} Bacteria
–
–
–
–
–
–
–
–
Pseudomonas aeruginosa
Vibrio cholerae
Yersinia pestis (PLAGUE! )
Enterobacter aerogenes
E. coli
Klebsiella pneumoneae
Proteus
Serratia
66
Aminoglycocide SE
• Highly polar (cationic) molecules, usually
prevents GI absorption
• Renally eliminated
– Ototoxicity
– Nephrotoxicity
• Neomycin-used topically,
hepatic failure
• Streptomycin-used in TB
orally
for
67
50s Inhibitors
• All 50s inhibitors binds irreversibly to
50s subunit, inhibiting translocation
(peptidyl transferase
– Therefore, giving ≥2 of these agents is
redundant
• Generally bacteriostatic (cidal @ high
doses)
68
Macrolides
• Azalides:
– Azithromycin (Zithromax®)
• Ketolides:
– Telithromycin (Ketek®)
• Macrolides:
– Clarithromycin (Biaxin®)
– Dirithromycin (Dynabac®)
– Erythromycin (Ery-Tab®)
69
Macrolide Spectrum
• Chlamydia (Erythro drug of choice in
pregnancy)
• Mycoplasma pneumoniae
– Ureaplasma urealyticum
•
•
•
•
Legionella pneumophila
Treponema pallidum (Syphillis)
Gram (+) cocci
Gram (+) bacilli
70
Macrolide Spectrum
• Clarithro>erythro
– Chlamydia, Legionella, Ureaplasma H. flu
• Azithro<erythro
– Staph, Strep
• Azithro>erythro
– H. flu, moraxella catarrhalis (why used for
pneumonia)
71
Macrolide SE
• Erythro destroyed by gastric acid
– Enteric coated or esterified forms
• Azithro concentrates in neutrophils,
macrophages, fibroblasts
• Erythro Azithro=hepatic;
clarithro=renal
• SE:
– NVD, cholestatic jaundice (estolate salterythro), Erythro & clarithro go through
CYP450
72
Lincomycins
• Clindamycin (Cleocin®)
• Lincomycin (Lincocin®)
73
Lincomycin Spectrum
•
•
•
•
•
Gram {+} aerobes
Gram {+} anaerobes
Gram {-} anaerobes
NO gram {-} aerobic coverage
Think of these as 2nd-line penicillins
74
Lincomycin SE
•
•
•
•
•
Rash
Neutropenia
Thrombocytopenia
Erythema multiforme (rare)
Pseudomembranous colitis
75
Chloramphenicol
• Broad spectrum against Gram {+}, Gram
{-}, and anaerobes.
• Can be extremely toxic
–
–
–
–
Dose-related revesible anemia
Hemolytic anemia in G6PD deficiency
Dose-independent aplastic anemia
“Grey baby syndrome” caused by drug
accumulation leading to cyanosis,
cardiovascular collapse and eventual death
76
Streptogramins
• Quinupristin/Dalfopristin (Synercid®)
– Dalfopristin inhibits early phase of protein
synthesis
– Quinupristin inhibits late phase of protein
synthesis
– Ratio 70% dalfopristin/30% quinupristin
• Major use is for VRE Enterococcus
faecium
(NO
coverage
against
enterococcus faecalis)
77
Oxazolidinones
• Linezolid (Zyvox®)
78
Linezolid
• Linezolid binds to a site on the bacterial
23S ribosomal RNA of the 50S subunit
and prevents the formation of a
functional 70S initiation complex
• Monoamine Oxidase Inhibition
– Linezolid is a reversible, nonselective
inhibitor of monoamine oxidase. Therefore,
linezolid has the potential for interaction
with adrenergic and serotonergic agents.
• Used in VRE and other severe infections
79
Cell Membrane
Inhibitors
80
Cell Membrane Inhibitors
• Daptomycin (Cubicin®)
• Unique mechanism of action that it binds
to bacterial membranes and causes a
rapid depolarization of membrane
potential which leads to inhibition of
protein, DNA, and RNA synthesis
• Used in antibiotic resistant MRSA, VRE,
and linezolid-resistant strains
• Can cause myalgias
81
Take Home Messages
• Regarding mechanism of action: Know its
major effect (cell wall vs. ribosomal)
• Regarding side effects: Know what will
kill (or maim) a person, or something
totally unique to that drug
• Regarding coverage: Know broad classes
(Gram, anaerobic)
• Regarding drugs: You will NEVER know
everything about pharmacology, so don’t
try to!
82
The End
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